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WO2019150993A1 - Appareil et procédé de détermination - Google Patents

Appareil et procédé de détermination Download PDF

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Publication number
WO2019150993A1
WO2019150993A1 PCT/JP2019/001483 JP2019001483W WO2019150993A1 WO 2019150993 A1 WO2019150993 A1 WO 2019150993A1 JP 2019001483 W JP2019001483 W JP 2019001483W WO 2019150993 A1 WO2019150993 A1 WO 2019150993A1
Authority
WO
WIPO (PCT)
Prior art keywords
unit
determination
penetration hole
tip
suction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2019/001483
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English (en)
Japanese (ja)
Inventor
真島　雅尚
洋一 青木
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Konica Minolta Inc
Original Assignee
Konica Minolta Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Konica Minolta Inc filed Critical Konica Minolta Inc
Priority to JP2019569001A priority Critical patent/JPWO2019150993A1/ja
Publication of WO2019150993A1 publication Critical patent/WO2019150993A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/648—Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence

Definitions

  • the present invention relates to an inspection cartridge determination apparatus and determination method.
  • SPFS Surface Plasmon-field enhanced Fluorescence Spectroscopy
  • a detection chip having a metal film that is disposed on the prism so as to be exposed in the unit and to which a capturing body (for example, a primary antibody) is fixed is used.
  • the liquid containing the substance to be detected is provided on the metal film, the substance to be detected is captured by the capturing body (primary reaction).
  • a capturing body for example, a secondary antibody
  • the target substance is labeled with the fluorescent substance (secondary reaction).
  • the fluorescent substance that labels the substance to be detected is excited by the electric field enhanced by SPR and emits fluorescence.
  • the SPFS device can detect the presence or amount of the substance to be detected by detecting the emitted fluorescence.
  • a cartridge for holding a specimen containing a substance to be detected is used (for example, refer to Patent Documents 2 and 3). Blood or the like is used as the sample, and the sample remains in the cartridge after the analysis is completed. Therefore, if a cartridge once used is reused, there is a high possibility that an erroneous analysis result is caused by contamination.
  • the cartridges disclosed in Patent Document 2 and Patent Document 3 can be used even in a disposable manner. However, even if the cartridge is made disposable, the risk of reuse cannot be avoided unless it can be instantly distinguished whether it is used or unused.
  • Patent Document 4 there is a method of giving an irreversible physical change to the inspection cartridge.
  • an irreversible variable portion provided in the cartridge is subjected to an irreversible physical change after use of the cartridge, and whether or not such a physical change has occurred is determined to determine whether it is used or unused. doing.
  • various other devices such as a change inducing unit, a discriminating unit, and a detecting unit are provided. It is necessary to provide the part. Therefore, there is a need for an inspection cartridge that can reliably determine whether it has been used or not, and that has as simple an equipment as possible.
  • an object of the present invention is to provide a determination device and a determination method for easily and surely determining whether an inspection cartridge has been used or not.
  • the present invention provides determination devices and determination methods shown in, for example, the following [1] to [21].
  • a test cartridge having a reagent well in which a reagent is stored, a sealing seal that seals the reagent well, and a penetration hole determination that determines whether or not a penetration hole exists in the sealing seal
  • a determination apparatus for determining whether or not the inspection cartridge is used comprising a use determination unit for determining that the inspection cartridge is unused.
  • a determination device further including a suction / discharge section capable of sucking or discharging gas, and a pressure measurement section for measuring a pressure value in the suction / discharge section, wherein the penetration hole determination section is formed by the pressure measurement section.
  • the measured pressure value is larger than a predetermined threshold value, it is determined that the penetration hole does not exist, and when the pressure value measured by the pressure measurement unit is a value equal to or smaller than the predetermined threshold value, the penetration hole [1]
  • the determination apparatus according to [1], in which it is determined that exists.
  • the suction discharge unit includes a pipette tip, and the pressure measurement unit measures an atmospheric pressure value in the pipette tip or a pressure difference before and after a suction discharge operation by the suction discharge unit.
  • the penetration hole determination unit determines whether or not the penetration hole exists in a state where the sealing surface of the sealing seal and the tip of the suction / discharge unit are separated by a predetermined distance.
  • the determination apparatus according to [2] or [3] that performs determination.
  • the determination apparatus according to [2] or [3], wherein the determination as to whether or not the penetration hole exists is performed when the operations shown in FIG.
  • the penetration hole determination unit determines whether or not the penetration hole exists in a state where the distance between the tip of the suction / discharge unit and the sealing surface of the sealing seal is within a predetermined value.
  • a suction / discharge section capable of sucking or discharging gas, a pressure measuring section for measuring a pressure value in the suction / discharge section, and a tip of the suction / discharge section in a direction perpendicular to a sealing surface of the sealing seal
  • a penetrating hole determining section wherein the sealing surface of the sealing seal and the tip of the suction / discharge section are separated by a predetermined distance.
  • the pressure measurement unit measures the pressure value in the suction / discharge unit, and if the pressure value in the suction / discharge unit is larger than a predetermined threshold, the first determination is performed to determine that the through hole does not exist.
  • the penetrating hole determining unit determines that the sealing surface of the sealing seal and the suction discharge are more effective than the first determining only when it is determined in the first determining that the penetrating hole does not exist.
  • Measuring the pressure value in the suction and discharge part more if the pressure value in the suction and discharge part is greater than a predetermined threshold, performs a second determination to determine that the penetration hole does not exist, the penetration hole determination part,
  • the determination apparatus according to [1], wherein the second determination is repeatedly performed until it is determined that the through hole does not exist or until the tip of the suction / discharge portion moves a predetermined distance.
  • the penetration hole determination unit uses the pressure value obtained by adding or subtracting a predetermined value to the pressure value measured in the first determination, the predetermined threshold value used when performing the second determination.
  • the determination apparatus according to [7].
  • the suction / discharge unit includes a pipette tip, and the pressure measurement unit measures an atmospheric pressure value in the pipette tip or a pressure difference before and after a suction / discharge operation by the suction / discharge unit [7] or [ 8].
  • the determination apparatus according to any one of [1] to [9], wherein the inspection cartridge includes a plurality of reagent wells.
  • the penetrating hole determination unit determines whether or not the penetrating hole exists in the sealing seal with respect to only one of the reagent wells among the plurality of reagent wells.
  • the determination apparatus described.
  • the plurality of sealing seals that seal each of the plurality of reagent wells are at least two or more different types of sealing seals, and the predetermined threshold value is different for each type of sealing seal.
  • the determination apparatus according to [10].
  • the determination apparatus includes a storage unit that stores the predetermined threshold in the plurality of sealing seals that seal each of the plurality of reagent wells.
  • the inspection cartridge includes an information recording unit in which information on the predetermined threshold is registered on a surface of the inspection cartridge, and a reading unit that reads information of the information recording unit. apparatus.
  • the penetration hole determination unit determines that the penetration hole does not exist when the contact sensor that determines whether or not the seal seal is in contact with the seal seal, and the contact sensor The determination device according to [1], in which it is determined that the penetration hole exists when the seal seal is not contacted. [18] The determination device according to [1], wherein the penetration hole determination unit determines whether or not the penetration hole exists by irradiating a laser capable of determining the presence or absence of the penetration hole. [19] The penetrating hole determining unit enables the photographing unit that images the inspection cartridge including the reagent well and the penetrating hole determining unit to determine whether or not the penetrating hole exists.
  • the determination apparatus further including an image analysis unit that analyzes an image captured by the imaging unit.
  • the test cartridge has a sample injection well for injecting a sample, in addition to the reagent well, and injects blood as the sample into the sample injection well.
  • the determination apparatus as described in any one of. [21] A determination method for determining whether or not a test cartridge having a reagent well in which a reagent is stored is used, is the reagent well sealed with a sealing seal, and does the sealing seal have a through hole? When the penetration hole is present in the sealing seal, the inspection cartridge is determined to be used by the penetration hole determination step for determining whether or not and the penetration hole determination step is performed. A determination method including a use determination step of determining that the inspection cartridge is unused when no through hole is present.
  • FIG. 1 is a schematic diagram showing the configuration of the SPFS apparatus according to the first embodiment.
  • FIG. 2A is a plan view of the inspection cartridge.
  • FIG. 2B is a cross-sectional view taken along line AA in FIG. 2A.
  • FIG. 2C is a cross section taken along line BB in FIG. 2A.
  • FIG. 3 is a schematic cross-sectional view of another form of the inspection cartridge.
  • FIG. 4 is a flowchart showing the operation of the SPFS apparatus according to the first embodiment.
  • FIG. 5A is a flowchart showing the contents of step S120 (confirmation of used cartridge) in the first embodiment.
  • FIG. 5B is a flowchart showing the content of step S130 (acquisition of first position information) in the first embodiment.
  • FIG. 5C is a flowchart showing the content of step S140 (acquisition of second position information) in the first embodiment.
  • FIG. 6A is a diagram illustrating a partial configuration of the SPFS apparatus according to the second embodiment.
  • FIG. 6B is a flowchart showing the contents of step S220 (confirmation of used cartridge) in the second embodiment.
  • FIG. 7A is a diagram illustrating a partial configuration of the SPFS apparatus according to the third embodiment.
  • FIG. 7B is a flowchart showing the contents of step S320 (confirmation of used cartridge) in the third embodiment.
  • FIG. 8A is a diagram illustrating a partial configuration of the SPFS apparatus according to the fourth embodiment.
  • FIG. 8B is a flowchart showing the contents of step S420 (confirmation of used cartridge) in the fourth embodiment.
  • FIG. 1 is a schematic diagram showing a configuration of a surface plasmon excitation enhanced fluorescence analyzer (SPFS apparatus) 100 according to an embodiment of the present invention.
  • the SPFS apparatus (reaction apparatus) 100 includes a liquid feeding unit 110 including a pipette 111 and a pipette moving unit 112, a transport unit 120 including a cartridge holder 121, a position information acquisition unit 130, an optical unit The irradiation unit 140, the light detection unit 150, and the control unit 160 are included.
  • the SPFS device 100 is used in a state where the inspection cartridge (accommodating chip, reaction chip) 10 is mounted on the cartridge holder 121. Therefore, the inspection cartridge 10 will be described first, and then each component of the SPFS apparatus 100 will be described.
  • FIG. 2 is a diagram illustrating a configuration of the inspection cartridge 10.
  • 2A is a plan view of the inspection cartridge 10, FIG.
  • FIG. 2B is a cross-sectional view taken along line AA shown in FIG. 2A
  • FIG. 2C is a cross-sectional view taken along line BB shown in FIG. 2A.
  • FIG. 3 is a schematic cross-sectional view showing another form of the inspection cartridge 10.
  • the inspection cartridge 10 includes a reaction region 41 and a reagent storage region 42.
  • the reaction region 41 includes the prism 20 including the incident surface 21, the film formation surface 22, and the emission surface 23, the metal film 30, the flow channel lid 40, the flow channel groove 43, the first through hole 44, and the second through hole.
  • a hole 45, a flow path 60, an injection part 70, and a storage part 80 are included.
  • the reagent storage area 42 includes reagent / sample wells 46a to 46h.
  • the reagent storage area 42 is provided with one or more reagent / sample wells 46a to 46h for storing reagents and the like.
  • the reagent / specimen wells 46a to 46h are concave portions whose surfaces are opened.
  • reagent / sample wells 46a to 46h a labeling solution used for the secondary reaction, a washing solution, and the like are stored.
  • a labeling solution used for the secondary reaction a washing solution, and the like are stored.
  • 46a is a washing solution
  • 46b is a waste solution
  • 46c is a labeling solution used for the secondary reaction
  • 46d to 46g are various reaction reagents (reaction reagents A to D)
  • 46h is a specimen.
  • the number and type of reagent / sample wells are not limited to this.
  • the volume in the well may vary depending on the amount of the cleaning solution, waste solution, and reagent, but in a state where each reagent contains a reaction reagent or cleaning solution, the well surface should be aligned at the same height. It is desirable that the inner volume is adjusted.
  • the metal film 30 and the flow path lid 40 are disposed on the film formation surface 22 of the prism 20.
  • the prism 20, the metal film 30, and the channel lid 40 form a channel 60 (accommodating portion) through which liquid flows.
  • the flow path 60 is disposed directly or via the metal film 30 on the film formation surface 22 of the prism 20.
  • the inspection cartridge 10 may be a reusable cartridge or a disposable cartridge.
  • the inspection cartridge 10 is a disposable cartridge.
  • the liquid flowing in the flow path 60 include a specimen (for example, blood, serum, plasma, urine, nasal fluid, saliva, semen, etc.) containing a substance to be detected, and a capturing body labeled with a fluorescent substance. Labeling solution, washing solution, etc. are included.
  • the reagent wells 46a to 46g are covered with the sealing seal 11. Thereby, even if reagents are stored in the reagent wells 46a to 46g before the test cartridge 10 is used, it is possible to prevent the reagents from spilling. As will be described later, after the test cartridge 10 is used, one or more through holes are formed in the sealing seal 11, but by reducing the size of the through holes, Spilling of reagent or waste liquid is also prevented to some extent by the sealing seal 11.
  • the material and thickness of the sealing seal 11 are not particularly limited as long as each reagent well 46a to 46g can be sealed and can be penetrated by the pipette tip 170.
  • Examples of the material of the sealing seal 11 include polyethylene terephthalate (PET), aluminum, (AL), polyethylene (PE), low density polyethylene (LDPE), linear low density polyethylene (LLDPE), biaxially oriented polypropylene ( OPP), unstretched polypropylene (CPP), nylon (NY), and ethylene vinyl acetate copolymer (EVA) are included.
  • PET polyethylene terephthalate
  • PE polyethylene
  • PE low density polyethylene
  • LLDPE linear low density polyethylene
  • OPP biaxially oriented polypropylene
  • CPP unstretched polypropylene
  • nylon NY
  • EVA ethylene vinyl acetate copolymer
  • the thickness of the sealing seal 11 is, for example, 10 to 200 ⁇ m.
  • the sealing seal 11 may be a laminate of a plurality
  • Examples of the laminate film include overprinting coat 1 ⁇ m / AL 20 ⁇ m / sealant film 35 ⁇ m, OP coat 3 ⁇ m / AL 30 ⁇ m / CPP 3 ⁇ m, PET 14 ⁇ m / AL 20 ⁇ m / sealant film 8 ⁇ m.
  • Examples of sealant film materials include polyethylene (PE), low density polyethylene (LDPE), linear low density polyethylene (LLDPE), biaxially oriented polypropylene (OPP), unstretched polypropylene (CPP), and ethylene vinyl acetate.
  • PE polyethylene
  • LDPE low density polyethylene
  • LLDPE linear low density polyethylene
  • OPP biaxially oriented polypropylene
  • CPP unstretched polypropylene
  • ethylene vinyl acetate ethylene vinyl acetate.
  • a polymer (EVA) and polyvinyl chloride (PVC) are included.
  • the means for joining the sealing seal 11 to the test cartridge 10 is capable of sealing the reagent wells 46a to 46g and has a joining strength that does not peel when the pipette tip 170 is inserted into the sealing seal 11. If it can ensure, it will not specifically limit.
  • the sealing seal 11 is joined to the inspection cartridge 10 by fusion or double-sided adhesive tape.
  • the sealing seal 11 may be joined to each well independently, or the sealing seal 11 may be joined to the entire surface so as to include all the reagent wells 46a to 46g. In any case, it is desirable that the joint between the sealing seal 11 and the test cartridge 10 is at a position not over the reagent wells 46a to 46g.
  • the prism 20 is made of an insulator that is transparent to the excitation light ⁇ . As described above, the prism 20 has the entrance surface 21, the film formation surface 22, and the exit surface 23. The incident surface 21 allows the excitation light ⁇ from the light irradiation unit 140 to enter the prism 20. A metal film 30 is disposed on the film formation surface 22. In the present embodiment, the excitation light ⁇ incident on the inside of the prism 20 is applied to the metal film 30 where the substance to be detected is captured. The excitation light ⁇ is reflected on the back surface of the metal film 30 to become reflected light ⁇ . More specifically, the excitation light ⁇ is reflected at the interface (deposition surface 22) between the prism 20 and the metal film 30 to become reflected light ⁇ . The emission surface 23 emits the reflected light ⁇ to the outside of the prism 20.
  • the shape of the prism 20 is not particularly limited.
  • the prism 20 is a pillar having a trapezoidal bottom surface.
  • the surface corresponding to one base of the trapezoid is the film formation surface 22, the surface corresponding to one leg is the incident surface 21, and the surface corresponding to the other leg is the emission surface 23.
  • the trapezoid serving as the bottom surface is preferably an isosceles trapezoid. Thereby, the entrance surface 21 and the exit surface 23 are symmetric, and the S wave component of the excitation light ⁇ is less likely to stay in the prism 20.
  • the incident surface 21 is formed so that the excitation light ⁇ does not return to the light irradiation unit 140.
  • the light source of the excitation light ⁇ is a laser diode (hereinafter also referred to as “LD”)
  • LD laser diode
  • the angle of the incident surface 21 is set so that the excitation light ⁇ does not enter the incident surface 21 perpendicularly in the scanning range centered on the enhancement angle.
  • the “enhancement angle” refers to scattered light having the same wavelength as the excitation light ⁇ emitted above the inspection cartridge 10 when the incident angle of the excitation light ⁇ with respect to the metal film 30 is scanned (hereinafter referred to as “plasmon scattered light”).
  • the angle between the incident surface 21 and the film formation surface 22 and the angle between the film formation surface 22 and the emission surface 23 are both about 80 °.
  • the angle of increase is generally determined by the design of the inspection cartridge 10.
  • the design factors are the refractive index of the prism 20, the refractive index of the metal film 30, the film thickness of the metal film 30, the extinction coefficient of the metal film 30, the wavelength of the excitation light ⁇ , and the like.
  • the enhancement angle is shifted by the substance to be detected trapped on the metal film 30, but the amount is less than several degrees.
  • the prism 20 has a considerable amount of birefringence.
  • the material of the prism 20 include insulating resin and glass.
  • the material of the prism 20 is preferably a resin having a refractive index of 1.4 to 1.6 and a small birefringence.
  • the metal film 30 is disposed so as to be exposed to at least a part of the flow path 60 on the film formation surface 22 of the prism 20.
  • the metal film 30 causes an interaction (SPR) between the photon of the excitation light ⁇ incident on the film formation surface 22 under total reflection conditions and the free electrons in the metal film 30, and is locally on the surface of the metal film 30.
  • In-situ light commonly referred to as “evanescent light” or “near-field light” can be generated.
  • the material of the metal film 30 is not particularly limited as long as it is a metal capable of generating SPR.
  • the material of the metal film 30 include gold, silver, copper, aluminum, and alloys thereof.
  • the metal film 30 is a gold thin film.
  • the method for forming the metal film 30 is not particularly limited. Examples of the method for forming the metal film 30 include sputtering, vapor deposition, and plating.
  • the thickness of the metal film 30 is not particularly limited, but is preferably 30 to 70 nm.
  • a capturing body for capturing a substance to be detected is fixed on the surface of the metal film 30.
  • the substance to be detected can be selectively detected.
  • the capturing body is uniformly fixed to a predetermined region on the metal film 30.
  • the region where the capturing body is fixed serves as a reaction field where a primary reaction and a secondary reaction described later occur.
  • the capturing body fixed to the metal film 30 is exposed in the flow path 60.
  • the type of capturing body is not particularly limited as long as it can capture the substance to be detected.
  • the capturing body is an antibody or a fragment thereof that can specifically bind to the substance to be detected.
  • the flow path lid 40 is disposed on the film formation surface 22 and is a part constituting the reaction region 41 as described above.
  • the reaction region 41 is a region for performing a primary reaction and a secondary reaction described later.
  • the reagent storage area 42 is an area in which a labeling solution used for the secondary reaction, a cleaning solution used for cleaning, and the like are stored.
  • a flow channel groove 43 serving as a flow channel (accommodating portion) 60 is formed on the back surface of the reaction region 41 in the flow channel lid 40.
  • a first through hole 44 serving as the injection portion 70 and a second through hole 45 serving as the storage portion 80 are opened on the front and back surfaces of the reaction region 41, respectively.
  • Both ends of the flow channel 43 are connected to the first through hole 44 and the second through hole 45, respectively.
  • the channel groove 43, the first through hole 44, and the second through hole 45 become the channel 60, the injection unit 70, and the storage unit 80, respectively, by stacking the prism 20, the metal film 30, and the channel lid 40 in this order. .
  • the channel lid 40 is preferably made of a material that is transparent to the fluorescence ⁇ emitted from the metal film 30 and the plasmon scattered light ⁇ .
  • An example of the material of the flow path lid 40 includes a resin.
  • the flow path cover 40 may be formed of an opaque material as long as the portion from which the fluorescent ⁇ and the plasmon scattered light ⁇ are extracted is transparent to the fluorescent ⁇ and the plasmon scattered light ⁇ .
  • the channel lid 40 is bonded to the prism 20 or the metal film 30 by, for example, adhesion using a double-sided tape or an adhesive, laser welding, ultrasonic welding, or pressure bonding using a clamp member.
  • the inspection cartridge 10 ′ may have a well (accommodating portion) 60 ′ instead of the flow path 60.
  • liquid is injected or removed from the opening of the well (accommodating portion) 60 ′.
  • the excitation light ⁇ enters the prism 20 at the incident surface 21.
  • the excitation light ⁇ that has entered the prism 20 is applied to the metal film 30 at a total reflection angle (an angle at which SPR occurs).
  • a total reflection angle an angle at which SPR occurs.
  • This localized field light excites a fluorescent substance that labels the substance to be detected present on the metal film 30 and emits fluorescence ⁇ .
  • the SPFS device 100 detects the presence or amount of the substance to be detected by measuring the amount of fluorescence ⁇ emitted from the fluorescent substance.
  • the SPFS device 100 includes the liquid feeding unit 110, the transport unit 120, the position information acquisition unit 130, the light irradiation unit 140, the light detection unit 150, and the control unit 160.
  • the inspection cartridge 10 can be held by the cartridge holder 121 of the transport unit 120.
  • the liquid feeding unit 110 includes a pipette 111, a pipette moving unit 112, and a liquid feeding pump drive mechanism 113.
  • the liquid feeding unit 110 injects a sample into the flow path 60 of the test cartridge 10 held in the cartridge holder 121, or a liquid such as a labeling solution or a cleaning solution stored in the reagent storage region 42 of the test cartridge 10 in the reaction region. 41 in the channel 60.
  • the liquid feeding unit 110 discharges the liquid from the flow path 60 and stirs the liquid in the flow path 60.
  • the liquid feeding unit 110 is used in a state where the pipette tip 170 is attached to the pipette nozzle 116 of the pipette 111. It should be noted that the pipette tip 170 is preferably replaceable from the viewpoint of preventing contamination of impurities.
  • the pipette 111 sucks the liquid when injecting the liquid into the flow path 60 or removing the liquid from the flow path 60.
  • the pipette 111 includes a syringe 114, a plunger 115 that can reciprocate inside the syringe 114, and a pipette nozzle 116 connected to the syringe 114. Further, the pipette 111 can quantitatively suck and discharge the liquid by the reciprocating motion of the plunger 115. Thereby, the pipette 111 can inject liquid into the flow path 60 or remove the liquid from the flow path 60. In addition, the pipette 111 can stir the liquid in the flow path 60 by repeatedly sucking and discharging the liquid.
  • the pipette moving unit 112 moves the pipette nozzle 116 in order to suck liquid into the pipette tip 170 and discharge the liquid from the pipette tip 170.
  • the pipette moving unit 112 freely moves the pipette nozzle 116 in the axial direction (for example, the vertical direction) of the pipette nozzle 116.
  • the pipette moving unit 112 includes, for example, a solenoid actuator and a stepping motor.
  • the liquid feed pump drive mechanism 113 moves the plunger 115 to suck the external liquid into the pipette tip 170 or discharge the liquid inside the pipette tip 170 to the outside.
  • the liquid feed pump drive mechanism 113 includes a device for reciprocating the plunger 115 such as a stepping motor.
  • the stepping motor is preferable from the viewpoint of managing the remaining liquid amount of the inspection cartridge 10 because it can manage the liquid feeding amount and the liquid feeding speed of the pipette 111.
  • the liquid feeding unit 110 sucks various liquids from the reagent / sample wells 46a to 46h and injects them into the flow path 60 of the test cartridge 10.
  • the reciprocating motion of the plunger 115 with respect to the syringe 114 is repeated, so that the liquid in the flow path 60 in the inspection cartridge 10 is obtained.
  • Reciprocates, and the liquid in the flow path 60 is agitated.
  • the liquid in the channel 60 is again sucked by the pipette 111 and discharged to a waste liquid tank or the like not shown.
  • reaction with various liquids, washing, and the like can be performed, and a detection target substance labeled with a fluorescent substance can be arranged in the reaction field in the flow path 60.
  • the conveyance unit 120 conveys the inspection cartridge 10 to the detection position or the liquid feeding position, and holds the inspection cartridge 10.
  • the “detection position” is a position where the light irradiation unit 140 irradiates the inspection cartridge 10 with the excitation light ⁇ , and the light detection unit 150 detects the fluorescence ⁇ or the plasmon scattered light ⁇ generated accordingly.
  • the “liquid feeding position” is a position where the liquid feeding unit 110 injects liquid into the flow path 60 of the inspection cartridge 10 or removes the liquid in the flow path 60 of the inspection cartridge 10.
  • the transport unit 120 includes a cartridge holder 121 and a transport stage 122.
  • the cartridge holder 121 is fixed to the transfer stage 122 and holds the inspection cartridge 10 in a detachable manner.
  • the shape of the cartridge holder 121 is not particularly limited as long as it can hold the inspection cartridge 10 and does not disturb the optical paths of the excitation light ⁇ , fluorescence ⁇ , and plasmon scattered light ⁇ .
  • the shape of the cartridge holder 121 is configured such that the inspection cartridge 10 can be held with the flow path lid 40 interposed therebetween.
  • the transfer stage 122 moves the cartridge holder 121 in a certain direction and in the opposite direction (left and right direction on the paper surface of FIG. 1).
  • the transport stage 122 also has a shape that does not interfere with the optical paths of the excitation light ⁇ , fluorescence ⁇ , and plasmon scattered light ⁇ .
  • the transfer stage 122 is driven by, for example, a stepping motor.
  • the position information acquisition unit 130 acquires first position information (hereinafter also simply referred to as “first position information”) regarding the position of the tip of the pipette tip 170 with respect to the solid first reference unit 180a.
  • the position information acquisition unit 130 includes an air pressure sensor 131.
  • the air pressure sensor 131 is connected between the pipette nozzle 116 and the syringe 114.
  • the type of the air pressure sensor 131 is not particularly limited as long as the air pressure (pressure) in the pipette tip 170 can be measured. Examples of the type of the air pressure sensor 131 include a mechanical sensor using a Bourdon tube, an electronic sensor using a semiconductor, and the like.
  • the first position information is the air pressure in the pipette tip 170 when gas is sucked or discharged from the tip of the pipette tip 170 by changing the distance between the tip of the pipette tip 170 and the first reference portion 180a. Is obtained by measuring the change in the air pressure sensor 131. More specifically, first, the first pressure in the pipette tip 170 is measured in a state where the tip of the pipette tip 170 is separated from the solid first reference portion 180a.
  • the “first reference portion” means a reference position of the tip of the pipette tip 170 with respect to the solid.
  • the first reference portion 180a is not particularly limited as long as it is solid and its position is specified with high accuracy, and may be a part of the inspection cartridge 10 or a part of the SPFS device 100. Also good.
  • Examples of the first reference portion 180a included in the inspection cartridge 10 include the channel lid 40, the sealing seal 11, the prism 20 (the bottom surface of the channel 60), and the like.
  • examples of the first reference unit 180a included in the SPFS apparatus 100 include a transfer stage 122, a cartridge holder 121, and an arrangement surface on which the transfer stage 122 is arranged in the transfer unit 120 (portion located below the pipette nozzle 116). It may be.
  • the suction or discharge of the gas at the tip of the pipette tip 170 may be performed continuously or intermittently.
  • the gas is also discharged when measuring the second pressure.
  • the gas is sucked when the first pressure is measured, the gas is sucked also when the second pressure is measured.
  • the position information acquisition unit 130 can also acquire second position information (hereinafter also simply referred to as “second position information”) regarding the position of the tip of the pipette tip 170 with respect to the liquid second reference unit 18b.
  • the second position information is a change in the distance between the tip of the pipette tip 170 and the second reference portion 18b, and a change in the air pressure in the pipette tip 170 when gas is sucked or discharged from the tip of the pipette tip 170 is detected by the air pressure sensor 131. It is acquired by measuring by.
  • the “second reference portion” means a reference position of the tip of the pipette tip 170 with respect to the liquid.
  • the second reference portion 18b is not particularly limited as long as it is a liquid and its position is specified with high accuracy.
  • Examples of the second reference portion 18b include the liquid level of the liquid stored in the reagent / sample wells 46a to 46h, the liquid level of the liquid in the flow path 60, and the like.
  • the suction or discharge of the gas at the tip of the pipette tip 170 may be performed continuously or intermittently.
  • the air pressure (first pressure and second pressure) of the gas sucked or discharged from the tip of the pipette tip 170 in the operation for acquiring the first position information is changed from the tip of the pipette tip 170 in the operation for acquiring the second position information. It is preferable to be different from the air pressure (third pressure and fourth pressure) of the gas to be sucked or discharged.
  • the position information acquisition unit 130 acquires the first position information and the second position information
  • the pipette 111 sucks gas from the tip of the pipette tip 170, an operation for acquiring the first position information.
  • the air pressures (first pressure and second pressure) of the gas sucked from the tip of the pipette tip 170 in the above are the air pressures (third pressure and fourth pressure) of the gas sucked from the tip of the pipette tip 170 in the operation of acquiring the second position information. Pressure). Further, when the position information acquisition unit 130 acquires the first position information and the second position information, when the pipette 111 discharges gas from the tip of the pipette tip 170, the pipette tip in the operation of acquiring the first position information.
  • the air pressures (first pressure and second pressure) of the gas discharged from the tip of 170 are larger than the air pressures (third pressure and fourth pressure) of the gas discharged from the tip of the pipette tip 170 in the operation of acquiring the second position information.
  • the absolute values of the gas air pressures (first pressure and second pressure) in the operation for acquiring the first position information are the gas air pressures (third pressure and fourth pressure) in the operation for acquiring the second position information. ) Is greater than the absolute value.
  • the light irradiation unit 140 irradiates the excitation light ⁇ toward the incident surface 21 of the inspection cartridge 10 held by the cartridge holder 121. At the time of measuring the fluorescence ⁇ or the plasmon scattered light ⁇ , the light irradiation unit 140 emits only the P wave toward the incident surface 21 so that the incident angle with respect to the metal film 30 is an angle that causes SPR. .
  • the “excitation light” is light that directly or indirectly excites the fluorescent material.
  • the excitation light ⁇ is light that generates localized field light on the surface of the metal film 30 that excites the fluorescent material when the metal film 30 is irradiated through the prism 20 at an angle at which SPR occurs.
  • the light irradiation unit 140 includes a light source unit 141, an angle adjustment mechanism 142, and a light source control unit 143.
  • the light source unit 141 emits the collimated excitation light ⁇ having a constant wavelength and light amount so that the shape of the irradiation spot on the back surface of the metal film 30 is substantially circular.
  • the light source unit 141 includes, for example, a light source of excitation light ⁇ , a beam shaping optical system, an APC mechanism, and a temperature adjustment mechanism (all not shown).
  • the type of the light source is not particularly limited, and is, for example, a laser diode (LD).
  • Other examples of light sources include light emitting diodes, mercury lamps, and other laser light sources.
  • the light emitted from the light source is not a beam, the light emitted from the light source is converted into a beam by a lens, a mirror, a slit, or the like.
  • the light emitted from the light source is not monochromatic light, the light emitted from the light source is converted into monochromatic light by a diffraction grating or the like.
  • the light emitted from the light source is not linearly polarized light, the light emitted from the light source is converted into linearly polarized light by a polarizer or the like.
  • the beam shaping optical system includes, for example, a collimator, a band pass filter, a linear polarization filter, a half-wave plate, a slit, and a zoom means.
  • the beam shaping optical system may include all of these or a part thereof.
  • the collimator collimates the excitation light ⁇ emitted from the light source.
  • the band-pass filter turns the excitation light ⁇ emitted from the light source into narrowband light having only the center wavelength. This is because the excitation light ⁇ from the light source has a slight wavelength distribution width.
  • the linear polarization filter turns the excitation light ⁇ emitted from the light source into completely linearly polarized light.
  • the half-wave plate adjusts the polarization direction of the excitation light ⁇ so that the P-wave component is incident on the metal film 30.
  • the slit and zoom means adjust the beam diameter, contour shape, and the like of the excitation light ⁇ so that the shape of the irradiation spot on the back surface of the metal film 30 is a circle of a predetermined size.
  • the APC mechanism controls the light source so that the output of the light source is constant. More specifically, the APC mechanism detects the amount of light branched from the excitation light ⁇ with a photodiode (not shown) or the like.
  • the APC mechanism controls the input energy by a regression circuit, thereby controlling the output of the light source to be constant.
  • the angle adjustment mechanism 142 adjusts the incident angle of the excitation light ⁇ with respect to the metal film 30 (the interface between the prism 20 and the metal film 30 (film formation surface 22)).
  • the angle adjusting mechanism 142 relatively radiates the optical axis of the excitation light ⁇ and the cartridge holder 121 in order to irradiate the excitation light ⁇ at a predetermined incident angle toward a predetermined position of the metal film 30 via the prism 20. Rotate.
  • the angle adjusting mechanism 142 rotates the light source unit 141 around an axis (axis perpendicular to the paper surface of FIG. 1) orthogonal to the optical axis of the excitation light ⁇ .
  • the position of the rotation axis is set so that the position of the irradiation spot on the metal film 30 hardly changes even when the incident angle is scanned.
  • the angle at which the amount of plasmon scattered light ⁇ is maximum is the enhancement angle.
  • High intensity fluorescence ⁇ can be measured by setting the incident angle of the excitation light ⁇ to the enhancement angle or an angle in the vicinity thereof.
  • the basic incident condition of the excitation light ⁇ is determined by the material and shape of the prism 20 of the inspection cartridge 10, the film thickness of the metal film 30, the refractive index of the liquid in the flow channel 60, etc. The optimum incident condition varies slightly depending on the type and amount of the light and the shape error of the prism 20. For this reason, it is preferable to obtain an optimal enhancement angle for each measurement.
  • the light source control unit 143 controls various devices included in the light source unit 141 to control the emission of the excitation light ⁇ from the light source unit 141.
  • the light source control unit 143 includes, for example, a known computer or microcomputer including an arithmetic device, a control device, a storage device, an input device, and an output device.
  • the light detection unit 150 detects the amount of fluorescence ⁇ emitted from the vicinity of the surface of the metal film 30 on the flow path 60 side when the light irradiation unit 140 irradiates the metal film 30 of the inspection cartridge 10 with the excitation light ⁇ . To do. Further, as necessary, the light detection unit 150 also detects plasmon scattered light ⁇ generated by irradiation of the excitation light ⁇ to the metal film 30.
  • the light detection unit 150 includes a light receiving unit 151, a position switching mechanism 152, and a sensor control unit 153.
  • the light receiving unit 151 is disposed in the normal direction to the surface of the metal film 30 of the inspection cartridge 10.
  • the light receiving unit 151 includes a first lens 154, an optical filter 155, a second lens 156, and a light receiving sensor 157.
  • the first lens 154 is, for example, a condensing lens, and condenses light emitted from the metal film 30.
  • the second lens 156 is an imaging lens, for example, and forms an image of the light collected by the first lens 154 on the light receiving surface of the light receiving sensor 157.
  • the optical path between the first lens 154 and the second lens 156 is substantially parallel.
  • the optical filter 155 is disposed between the first lens 154 and the second lens 156.
  • the optical filter 155 guides only the fluorescence component to the light receiving sensor 157 and removes the excitation light component (plasmon scattered light ⁇ ) in order to detect the fluorescence ⁇ with a high S / N ratio.
  • Examples of the optical filter 155 include an excitation light reflection filter, a short wavelength cut filter, and a band pass filter.
  • the optical filter 155 is, for example, a filter including a multilayer film that reflects a predetermined light component, or a color glass filter that absorbs a predetermined light component.
  • the light receiving sensor 157 detects fluorescence ⁇ and plasmon scattered light ⁇ .
  • the light receiving sensor 157 has a high sensitivity capable of detecting weak fluorescence ⁇ from a very small amount of a substance to be detected.
  • the light receiving sensor 157 is, for example, a photomultiplier tube (PMT) or an avalanche photodiode (APD).
  • the position switching mechanism 152 switches the position of the optical filter 155 on or off the optical path in the light receiving unit 151. Specifically, when the light receiving sensor 157 detects the fluorescence ⁇ , the optical filter 155 is disposed on the optical path of the light receiving unit 151, and when the light receiving sensor 157 detects the plasmon scattered light ⁇ , the optical filter 155 is placed on the light receiving unit 151. Placed outside the optical path.
  • the sensor control unit 153 controls detection of an output value of the light receiving sensor 157, management of sensitivity of the light receiving sensor 157 based on the detected output value, change of sensitivity of the light receiving sensor 157 for obtaining an appropriate output value, and the like.
  • the sensor control unit 153 includes, for example, a known computer or microcomputer including an arithmetic device, a control device, a storage device, an input device, and an output device.
  • the controller 160 controls the liquid feed pump drive mechanism 113, the transport stage 122, the angle adjustment mechanism 142, the light source controller 143, the position switching mechanism 152, and the sensor controller 153.
  • the control unit 160 includes, for example, a known computer or microcomputer including an arithmetic device, a control device, a storage device, an input device, and an output device.
  • the penetration hole determining unit 161 determines whether or not there is a penetration hole in the sealing seal 11 on the reagent well based on the pressure in the pipette tip 170 and the like, as will be described later.
  • the penetration hole determination unit 161 is configured by a known computer or microcomputer including an arithmetic device, a control device, a storage device, an input device, and an output device.
  • the use determining unit 162 determines that the inspection cartridge has been used when the through hole determining unit 161 determines that the through hole exists, and determines that the through hole does not exist. In this case, it is determined that the inspection cartridge is unused.
  • the penetration hole determination unit 161 is configured by a known computer or microcomputer including an arithmetic device, a control device, a storage device, an input device, and an output device. (Detection operation of SPFS device) Next, the detection operation of the substance to be detected of the SPFS device 100 including the method for checking the used inspection cartridge and the detection method for detecting the position information of the tip of the pipette tip 170 according to the first embodiment will be described.
  • FIG. 4 is a flowchart illustrating an example of an operation procedure of the SPFS apparatus 100.
  • FIG. 5A is a flowchart showing the contents of the step of checking used cartridges (step S120 in FIG. 4)
  • FIG. 5B is a flowchart showing the contents of the step of acquiring first position information (step S130 in FIG. 4).
  • FIG. 5C is a flowchart showing the contents of the step of acquiring the second position information (step S140 in FIG. 4).
  • the primary antibody is immobilized on the metal film 30 as a capturing body.
  • a secondary antibody labeled with a fluorescent substance is used as a capturing body used for fluorescent labeling.
  • the first reference portion 180a is the bottom surface of the flow channel 60
  • the second reference portion 18b is the liquid surface in the reagent / sample well 46a-h, which is a well containing a sample (see FIG. 2B). .
  • the cleaning liquid contained in 46a is used first. Therefore, it is possible to determine whether the inspection cartridge 10 has been used or unused by determining whether or not there is a penetration hole only for 46a. That is, without determining whether or not the penetration holes exist in the sealing seals 11 of all the reagent wells 46a to 46g, the penetration holes exist only in the sealing seals 11 of one cleaning liquid well 46a. Whether or not the inspection cartridge 10 has been used can be determined simply by determining whether or not the inspection cartridge 10 has been used.
  • the present embodiment it is detected whether or not the penetration hole exists only for the sealing seal 11 on the cleaning liquid well 46a containing the cleaning liquid, but the present invention is not limited to this.
  • the presence or absence of a perforation hole may be detected with respect to a sealing seal on reagent wells other than 46a.
  • all the wells provided in the test cartridge 10 are detected.
  • the presence or absence of a penetration hole may be detected.
  • an expiration date may be set for the inspection cartridge 10. If there is an expiration date, for example, whether or not the inspection cartridge 10 is within the expiration date by reading a barcode or the like written in advance on the inspection cartridge 10 before installing the inspection cartridge 10 in the cartridge holder 121. Can be examined.
  • step S120 the used cartridge is confirmed (step S120).
  • the pipette nozzle 116 is lowered while discharging air from the tip of the pipette tip 170 (step S121).
  • the control unit 160 drives the liquid feeding pump drive mechanism 113 to advance the plunger 115 relative to the syringe 114, and continuously exhales air from the tip of the pipette tip 170.
  • the control unit 160 drives the pipette moving unit 112 to move the tip of the pipette tip 170 so as to approach the sealing seal 11 on the cleaning liquid well 46a.
  • step S122 it is determined whether or not there is a penetration hole in the sealing seal 11 (step S122). Specifically, in step S121 described above, the pressure in the pipette tip 170 is continuously measured during the operation of moving the tip of the pipette tip 170 so as to approach the sealing seal 11 on the cleaning liquid well 46a. . Therefore, the penetration hole determining unit 161 included in the control unit 160 determines whether or not the pressure value in the pipette tip 170 exceeds a preset threshold value. If the pressure value exceeds the threshold value, the penetration hole determination unit 161 determines that there is no penetration hole, and ends step S120. If the pressure value does not exceed the threshold value, the process proceeds to step S123.
  • the use determination unit 162 determines that the inspection cartridge 10 is unused. In this embodiment, it is determined whether or not the penetration hole exists only for the reagent well 46a. However, it may be determined whether or not the penetration hole exists for all the reagent wells 46a to 46g. .
  • the threshold value of the pressure value can be set to various values within a range where it can be determined whether or not there is a penetration hole.
  • a value determined by various experiments can be used.
  • the inspection cartridge 10 in which a penetration hole is made in the sealing seal 11 by the pipette tip 170 and the inspection cartridge 10 in which the penetration hole is not made are prepared, and the tip of the pipette tip 170 is sealed with respect to both inspection cartridges 10.
  • the seal 11 is brought close to the sealing surface of the sealing seal 11 from a certain distance away, and at the same time, air is discharged and the pressure in the pipette tip 170 is measured.
  • This operation is performed until the pipette tip 170 moves to a position on the seal surface.
  • the movement distance and pressure value of the pipette tip 170 are monitored, and the behavior of the movement distance and the pressure value is compared between the inspection cartridge 10 with the penetration hole and the inspection cartridge 10 with no penetration hole. Then, from the result of comparing the behavior, the pressure value of the portion having a clear difference in the pressure value, for the case where the penetration hole is made and the case where the penetration hole is not made, is detected to determine whether or not the penetration hole exists.
  • the pressure value threshold is not limited to this, and various methods such as various experiments may be used.
  • the threshold value of the pressure value can be set to a different value for each type of the sealing seal 11.
  • the penetration hole determination unit 161 stores, for example, a threshold value of the pressure value of each sealing seal 11 in advance, and uses a number or the like set in advance for each sealing seal 11. It can comprise so that the threshold value of the pressure value for every seal
  • each inspection cartridge 10 has a recording unit such as a barcode in which a threshold value of the pressure value is registered on the surface of the inspection cartridge 10. You may comprise so that the penetration hole determination part 161 recognizes the threshold value of a pressure value by reading a recording part.
  • step S123 it is determined whether or not the moving distance of the pipette nozzle 116 (the descending distance in this embodiment) exceeds a preset penetration hole detection range. Specifically, in step S122 described above, when the pressure value does not exceed the threshold value, the pipette nozzle 116 continues to be lowered (an operation to move the tip of the pipette tip 170 closer to the seal surface). When the moving distance of the pipette nozzle 116 does not exceed a penetration hole detection range described later, the control unit 160 returns to step S121 and continues to lower the pipette nozzle 116 while exhaling air. When the moving distance of the pipette nozzle 116 exceeds the penetration hole detection range, the penetration hole determination unit 161 determines that there is a penetration hole and ends step S120.
  • the use determination unit 162 determines that the inspection cartridge 10 has been used. As a result, the operator can appropriately replace the inspection cartridge 10 with an unused one.
  • the penetration hole detection range can be set at an arbitrary distance depending on the configuration of the apparatus.
  • step S120 when it is determined that the inspection cartridge 10 has been used, the apparatus may be stopped and a warning may be displayed. Specifically, at the same time when the use determination unit 162 determines that the inspection cartridge 10 has been used, the control unit 160 stops the pipette nozzle 116 from descending. Further, a pop-up warning is displayed on an operation screen (not shown) to notify the operator that there is a penetration hole, that is, the inspection cartridge 10 has been used.
  • the timing for stopping the pipette nozzle 116 from dropping may be immediately after the control unit 160 determines that there is a penetration hole, or after determining that there is a penetration hole. Further, the pipette nozzle 116 may be further lowered. However, it is desirable to set the maximum distance for lowering the pipette nozzle 116 so that the tip of the pipette tip 170 does not reach the liquid surface of the cleaning liquid.
  • step S120 a method of continuously discharging air from the tip of the pipette tip 170 is employed.
  • a method of intermittently discharging air or a method of continuously or intermittently sucking air is employed. May be.
  • the absolute value of the pressure value is monitored with respect to the pressure in the pipette tip 170.
  • the operation of lowering the pipette nozzle 116, the operation of discharging air, and the operation of measuring the pressure in the pipette tip 170 are simultaneously performed to detect whether or not there is a penetration hole.
  • the present invention is not limited to this.
  • the operation of exhausting air and the operation of measuring pressure are performed at the same time, and while performing these operations, the operation of lowering the pipette nozzle is not performed and the air is exhausted.
  • the pipette nozzle may be lowered when the operation and the operation for measuring the pressure are not performed.
  • the above-described operation for discharging air, the operation for measuring pressure, and the operation for lowering the pipette nozzle may be repeated.
  • the pressure in the pipette tip 170 is measured while discharging air. At this time, if the pressure value is larger than a predetermined threshold value, it is determined that there is no penetration hole. If the pressure value is equal to or lower than the predetermined threshold value, the tip of the pipette tip 170 is brought close to the sealing surface of the sealing seal 11. Measure the pressure as well. Such an operation is repeated until it is determined that there is no penetration hole, or until it is lowered by a predetermined distance.
  • the predetermined distance is not particularly limited, but is adjusted so that the tip of the pipette tip 170 is closer to the liquid surface than the sealing surface of the seal 11 and the tip of the pipette tip 170 is not in contact with the liquid surface. It is desirable to be a distance.
  • the distance between the tip of the pipette tip 170 and the sealing surface of the sealing seal 11 is arranged to be a predetermined distance, and only once when arranged as such.
  • the operation of discharging air and the operation of measuring pressure may be performed to determine whether or not there is a penetration hole.
  • the first position information is acquired (step S130).
  • the first pressure in the pipette tip 170 is measured (step S131).
  • the control unit 160 drives the pipette moving unit 112 to move the tip of the pipette tip 170 to a position directly below the bottom surface (first reference unit 180a) of the flow channel 60.
  • the control unit 160 drives the liquid feed pump driving mechanism 113 to advance the plunger 115 relative to the syringe 114, and continuously exhales air from the tip of the pipette tip 170, while pipetting with the air pressure sensor 131.
  • a first pressure in the chip 170 is measured.
  • the control unit 160 drives the pipette moving unit 112 to place the tip of the pipette tip 170 at the bottom of the flow channel 60 (first reference unit 180a) rather than the step of measuring the first pressure (step S131). Move to the side. Then, the control unit 160 drives the liquid feed pump driving mechanism 113 to advance the plunger 115 relative to the syringe 114, and continuously exhales air from the tip of the pipette tip 170, while pipetting with the air pressure sensor 131. A second pressure in the chip 170 is measured.
  • a difference between the first pressure and the second pressure is obtained (step S133). Specifically, the control unit 160 obtains a difference between the first pressure and the second pressure by subtracting the second pressure (first pressure) from the first pressure (second pressure). At this time, the pipette moving unit 112 is driven until the difference between the first pressure and the second pressure becomes equal to or greater than a predetermined threshold, and the tip of the pipette tip 170 is moved to the bottom surface (first reference portion 180a) side of the flow channel 60. And the step of measuring the second pressure in the pipette tip 170 by the air pressure sensor 131 is repeated.
  • the controller 160 determines that the tip of the pipette tip 170 is close to the first reference portion 180a due to the difference between the first pressure and the second pressure, and the pipette tip with respect to the first reference portion 180a.
  • the position of the tip of 170 is detected. That is, the control unit 160 acquires the first position information of the tip of the pipette tip 170 with respect to the first reference unit 180a when the air pressure sensor 131 detects the air pressure.
  • step S133 it is also possible to determine whether or not there is a through hole in the sealing seal 11 by the same procedure as in step S133. That is, if the difference between the first pressure and the second pressure is greater than a predetermined threshold, it is determined that there is no penetration hole, and if the difference between the first pressure and the second pressure is less than the predetermined threshold, the penetration It can also be determined that a hole exists.
  • the air pressure is continuously discharged intermittently or intermittently from the tip of the pipette tip 170 and the tip of the pipette tip 170 is brought close to the first reference portion 180a.
  • the air pressure in the pipette tip 170 may be measured by the sensor 131. In this case, the air pressure before moving the pipette tip 170 becomes the first pressure. Further, the air pressure in the pipette tip 170 measured by the air pressure sensor 131 while the tip of the pipette tip 170 is brought close to the first reference portion 180a becomes the second pressure. Even in this case, the first position information can be acquired with high accuracy.
  • the step of removing the cleaning liquid from the metal film 30 is performed after the first position information is acquired (step S130) and before the step of determining the incident angle of the excitation light ⁇ (step S150).
  • step S141 the third pressure in the pipette tip 170 is measured.
  • the control unit 160 drives the pipette moving unit 112 to move the tip of the pipette tip 170 directly below the liquid level (second reference unit 18b) stored in the sample well 46h.
  • the control unit 160 drives the liquid feed pump driving mechanism 113 to advance the plunger 115 relative to the syringe 114, and continuously exhales air from the tip of the pipette tip 170, while pipetting with the air pressure sensor 131.
  • a third pressure in the chip 170 is measured.
  • the fourth pressure in the pipette tip 170 is measured (step S142). Specifically, the control unit 160 drives the pipette moving unit 112, and the liquid level of the liquid stored in the specimen well 46h at the tip of the pipette tip 170 than in the step of measuring the third pressure (step S141). Move to the (second reference portion 18b) side. Then, the control unit 160 drives the liquid feed pump driving mechanism 113 to advance the plunger 115 relative to the syringe 114, and continuously exhales air from the tip of the pipette tip 170, while pipetting with the air pressure sensor 131. A fourth pressure in the chip 170 is measured.
  • a difference between the third pressure and the fourth pressure is obtained (step S143).
  • the control unit 160 obtains a difference between the third pressure and the fourth pressure by subtracting the fourth pressure (third pressure) from the third pressure (fourth pressure).
  • the control part 160 detects the position of the front-end
  • the air pressure is continuously discharged intermittently or intermittently from the tip of the pipette tip 170, and the tip of the pipette tip 170 is brought close to the second reference portion 18b.
  • the air pressure in the pipette tip 170 may be measured by the sensor 131. In this case, the pressure before moving the pipette tip 170 is the third pressure. Further, the air pressure in the pipette tip 170 measured by the air pressure sensor 131 while the tip of the pipette tip 170 is brought close to the second reference portion 18b becomes the fourth pressure. Even in this case, the second position information can be acquired with high accuracy.
  • the first position information in order to reduce the amount of residual liquid on the metal film 30, it is preferable to obtain at least the first position information before sending the liquid onto the metal film 30. Further, in order to manage the amount of liquid adhering to the wall surface of the pipette tip 170, it is more preferable to acquire the second position information before sending the liquid.
  • the incident angle of the excitation light ⁇ is determined (step S150). Specifically, the control unit 160 operates the transport stage 122 to move the inspection cartridge 10 to the detection position. The controller 160 drives the sensor controller 153 to detect the plasmon scattered light ⁇ by the light receiving sensor 157 while driving the angle adjusting mechanism 142 to scan the incident angle of the excitation light ⁇ .
  • the angle at which the amount of plasmon scattered light ⁇ is maximized is defined as the incident angle (enhancement angle) of the excitation light ⁇ .
  • step S160 the substance to be measured in the specimen is reacted with the primary antibody (primary reaction; step S160).
  • the control unit 160 operates the transport stage 122 to move the container in which the specimen is stored directly below the pipette tip 170. Then, the tip of the pipette tip 170 is moved toward the container in which the specimen is stored, and the specimen is inhaled into the pipette tip 170.
  • the controller 160 operates the conveyance stage 122 to move the inspection cartridge 10 to the liquid feeding position. Then, the control unit 160 drives the pipette moving unit 112 based on the first position information, moves the tip of the pipette tip 170 into the injection unit 70, and injects the specimen into the flow channel 60.
  • the specimen is removed from the flow path 60.
  • the tip of the pipette tip 170 is brought close to the bottom surface of the flow channel 60 based on the first position information. Then, the sample is removed from the flow path 60 by inhaling the sample into the pipette tip 170. The removed specimen is injected into the reagent well 46b for storing the waste liquid.
  • the types of the specimen and the substance to be detected are not particularly limited.
  • the specimen include body fluids such as blood, serum, plasma, urine, nasal fluid, saliva, semen, and diluted solutions thereof.
  • substances to be detected include nucleic acids (such as DNA and RNA), proteins (polypeptides and oligopeptides), amino acids, carbohydrates, lipids, and modified molecules thereof.
  • the specimen may be reciprocated in the flow channel 60.
  • the tip of the pipette tip 170 is brought close to the bottom surface of the flow channel 60 based on the first position information.
  • the plunger 115 is reciprocated while the position of the tip of the pipette tip 170 is fixed. Accordingly, the sample can be reciprocated in the flow path 60 by repeatedly inhaling and discharging the sample with the pipette tip 170.
  • the sample is removed from the flow channel 60 by inhaling the sample into the pipette tip 170. The removed specimen is injected into the reagent well 46b for storing the waste liquid.
  • the metal film 30 is cleaned with a cleaning solution such as a buffer solution.
  • the control unit 160 moves the tip of the pipette tip 170 toward the cleaning liquid in the reagent well 46 a and causes the cleaning liquid to be sucked into the pipette chip 170.
  • the second position information is specified with high accuracy, the distance between the tip of the pipette tip 170 and the surface of the cleaning liquid and the distance between the tip of the pipette tip 170 and the bottom surface of the reagent well 46a are also high. It can be controlled accurately. Therefore, the cleaning liquid can be appropriately sucked into the pipette tip 170.
  • the control unit 160 drives the pipette moving unit 112 based on the second position information, moves the tip of the pipette tip 170 into the injection unit 70, and injects the cleaning liquid into the flow channel 60.
  • the washing liquid containing the substance that has not bound to the primary antibody is removed from the flow path 60.
  • the control unit 160 drives the pipette moving unit 112 to move the tip of the pipette tip 170 to the injection unit 70.
  • the tip of the pipette tip 170 is brought close to the bottom surface of the channel 60 to remove the cleaning liquid from the channel 60.
  • the tip of the pipette tip 170 is brought close to the prism 20 (metal film 30) based on the first position information, the amount of liquid remaining in the flow path 60 can be minimized.
  • the position of the tip of the pipette tip 170 when removing the cleaning liquid is preferably the same as the position of the tip of the pipette tip 170 in the step of removing the specimen from the flow path 60. Thereby, the amount of liquid remaining in the flow path 60 can be made constant.
  • the removed specimen is injected into the reagent well 46b for storing the waste liquid.
  • the target substance captured on the metal film 30 is labeled with a fluorescent substance (secondary reaction; step S170).
  • the control unit 160 moves the tip of the pipette tip 170 toward a reagent well (for example, reagent well 46c) in which a liquid (labeling solution) containing a capturing body labeled with a fluorescent substance is stored.
  • the labeling solution is inhaled into the pipette tip 170.
  • the second position information is specified with high accuracy, the distance between the tip of the pipette tip 170 and the surface of the labeling liquid, and the distance between the tip of the pipette tip 170 and the bottom surfaces of the reagent wells 46a to 46h. Distance can be detected with high accuracy.
  • the labeling solution can be appropriately inhaled into the pipette tip 170.
  • the control unit 160 drives the pipette moving unit 112 to move the tip of the pipette tip 170 into the injection unit 70 based on the first position information, and injects the labeling solution into the flow channel 60.
  • the detection target substance captured on the metal film 30 is labeled with a fluorescent substance by an antigen-antibody reaction.
  • the labeling liquid in the flow path 60 is removed, and the inside of the flow path 60 is cleaned with a cleaning liquid.
  • the position of the tip of the pipette tip 170 when removing the labeling liquid in the channel 60 is positioned based on the first position information described above. As a result, the amount of liquid remaining in the flow path 60 can be kept to a minimum and constant.
  • step S160 the order of the primary reaction (step S160) and the secondary reaction (step S170) is not limited to this.
  • a liquid containing these complexes may be provided on the metal film 30.
  • the specimen and the labeling solution may be provided on the metal film 30 at the same time.
  • a substance to be detected is detected (step S180). Specifically, the control unit 160 operates the transport stage 122 to move the inspection cartridge 10 to the detection position. Then, the sensor control unit 153 is driven to drive the metal film 30 (while the light source control unit 143 is driven and the excitation light ⁇ is irradiated to a predetermined position of the metal film 30 at the incident angle (enhancement angle) determined in step S150. The light receiving sensor 157 is controlled so as to detect the intensity of the fluorescence ⁇ emitted from the surface of the metal film 30 and the vicinity thereof.
  • control part 160 may measure a blank value before a secondary reaction (process S170).
  • the excitation light ⁇ is irradiated onto the metal film 30 at an enhancement angle, and the detection value of the light receiving sensor 157 is set as a blank value.
  • the amount of the fluorescence ⁇ indicating the amount of the substance to be detected in the sample is calculated by subtracting the blank value from the detection value of the fluorescence ⁇ .
  • the substance to be detected is detected using the SPFS apparatus by the procedure as described above.
  • the presence or absence of a hole in the sealing seal 11 is detected only on the sealing surface on the cleaning liquid well 46a, but may be detected on the sealing surface on other wells. It may be detected by a sealing surface on each well. However, even when the presence or absence of a hole is detected on the seal surface on any well, the tip of the pipette tip 170 is in contact with the liquid level of the liquid contained in the well during the operation of detecting the presence or absence of a hole. It is desirable not to reach it.
  • the first reference portion 180a is the bottom surface of the flow path 60, but is not limited thereto.
  • the first reference portion 180a is set at various locations in the inspection cartridge 10 or the SPSF device 100, such as a part of the transport stage 122, a part of the arrangement surface 650 where the transport stage 122 is disposed, and the top surface of the inspection cartridge 10. be able to.
  • the substance to be detected is detected using the SPFS device 100.
  • the SPFS device 100 Is merely an example, and measurement using an apparatus other than the SPFS apparatus 100 may be performed.
  • a device for measuring the concentration of red blood cells in blood or a device for detecting pathogenic bacteria present in a specimen Any inspection may be performed.
  • the SPFS device according to the second embodiment is implemented by a method for determining whether or not there is a through hole generated when the test cartridge 10 is used and determining whether the test cartridge 10 is used or not used.
  • the same components as those of the SPFS device 100 according to the first embodiment are denoted by the same reference numerals, description thereof is omitted, and different portions are mainly described.
  • FIG. 6A is a diagram illustrating a partial configuration of the SPFS apparatus according to the second embodiment.
  • the contact sensor unit 190 determines whether or not there is a penetration hole in the sealing seal 11.
  • the contact sensor 191 and the contact sensor moving unit 192 are connected by a sensor connection unit 193, and the contact sensor moving unit 192 and the contact sensor 191 are electrically connected to the control unit 160, respectively.
  • the contact sensor 191 may be anything as long as it can detect contact with the sealing seal 11. Although the shape and size are not particularly limited, it is preferably a bar-shaped contact sensor with a thin tip. In addition, when the tip portion for detecting contact is larger than the size of the penetration hole, the contact with the sealing seal 11 may be erroneously detected despite the presence of the penetration hole. It is desirable that the tip portion for detecting contact is smaller than the size of the penetration hole.
  • the contact sensor moving unit 192 is configured to freely move the contact sensor 191 in the vertical direction.
  • the contact sensor moving unit 192 includes, for example, a solenoid actuator and a stepping motor.
  • the sensor connection unit 193 may be formed of any member as long as the contact sensor 191 and the contact sensor moving unit 192 can be connected. However, a member capable of passing an electric signal or the like is desirable.
  • FIG. 6B is a flowchart showing the contents of the cartridge use determination operation process according to the second embodiment.
  • preparation for measurement is performed before the process shown in FIG. 6B.
  • the preparation method is the same as the method shown in step S110, but in this embodiment, the tip of the contact sensor 191 is set to a position immediately below the cleaning liquid well 46a containing the cleaning liquid instead of the pipette tip 170. To do.
  • contact determination is performed (step S222).
  • the penetration hole determination unit 161 determines whether or not the contact sensor 191 has contacted the sealing seal 11.
  • the range in which the contact sensor 191 is lowered at this time is not limited to this and can be set to various distances.
  • the penetration hole determination unit 161 determines that there is no penetration hole when the contact sensor 191 contacts the sealing seal 11, and determines that there is a penetration hole when the contact sensor 191 does not contact the sealing seal 11.
  • the use determination unit 162 determines that the inspection cartridge 10 is unused when the penetration hole determination unit 161 determines that there is no penetration hole, and the use determination unit 162 determines that the penetration hole is present when the penetration hole determination unit 161 determines that there is a penetration hole. 10 is determined to be used.
  • the SPFS device according to the third embodiment is different from the SPFS device 100 according to the first embodiment in a method for determining whether or not there is a penetration hole that occurs when the test cartridge 10 is used. Therefore, the same components as those of the SPFS device 100 according to the first embodiment are denoted by the same reference numerals, description thereof is omitted, and different portions are mainly described.
  • FIG. 7A is a diagram illustrating a partial configuration of the SPFS apparatus according to the third embodiment.
  • the laser unit 200 determines whether or not there is a penetration hole in the sealing seal 11.
  • the laser beam irradiation unit 201 and the laser beam detection unit 202 are electrically connected to the control unit 160, respectively.
  • the laser light detection unit 202 is located on the opposite side of the sealing surface of the sealing seal 11 from the laser light irradiation unit 201 and the sealing surface of the sealing seal 11 has a through hole It is desirable that the laser light irradiation unit 201 is positioned so that the irradiation port through which the laser light is irradiated, the penetration hole, and the laser light detection unit 202 are aligned.
  • the laser beam irradiation unit 201 is not particularly limited as long as it can determine whether or not there is a penetration hole in the sealing seal 11.
  • a laser beam irradiation unit 201 that can irradiate a laser beam that does not transmit the sealing seal 11 or a laser beam that transmits the sealing seal 11 but has a small amount of light is suitable.
  • the laser light detection unit 202 is not particularly limited as long as it can detect the laser light irradiated by the laser light irradiation unit 201.
  • the laser light detection unit 202 can detect an increase or decrease in the light amount of the laser light. Desirably configured. (Penetration hole judgment operation of SPFS device)
  • the cartridge use determination operation according to the third embodiment will be described focusing on the difference from the cartridge use determination operation of the SPFS device 100 according to the first embodiment.
  • FIG. 7B is a flowchart showing the contents of the cartridge use determination operation process in the third embodiment.
  • preparation for measurement is performed before the step shown in FIG. 7B.
  • the preparation method is the same as the method shown in step S110, but in this embodiment, the laser light irradiation unit 201 is set to be directly below the cleaning liquid well 46a containing the cleaning liquid, not the pipette tip 170. To do.
  • step S320 the process proceeds to the cartridge use determination operation step (step S320) in the third embodiment.
  • the control unit 160 irradiates the laser beam from the laser beam irradiation unit 201 toward the sealing surface of the sealing seal 11 on the cleaning liquid well 46a (step S321). At this time, the laser beam is irradiated toward the position where the through hole generated when the test cartridge 10 is used on the sealing surface of the sealing seal 11 on the cleaning liquid well 46a.
  • step S322 laser light detection is performed (step S322).
  • the laser light detection unit 202 detects the laser light irradiated toward the sealing surface of the sealing seal 11 on the cleaning liquid well 46a. For example, if the laser light does not pass through the sealing seal 11, the penetration hole determination unit 161 determines that there is no penetration hole when the laser light detection unit 202 does not detect the laser light, and the laser light detection unit performs laser processing. When light is detected, it is determined that there is a penetration hole.
  • the use determination unit 162 determines that the inspection cartridge 10 is unused when the penetration hole determination unit 161 determines that there is no penetration hole, and the use determination unit 162 determines that the penetration hole is present when the penetration hole determination unit 161 determines that there is a penetration hole. 10 is determined to be used.
  • the SPFS device according to the fourth embodiment is different from the SPFS device 100 according to the first embodiment in a method for determining whether or not there is a through hole generated when the test cartridge 10 is used. Therefore, the same components as those of the SPFS device 100 according to the first embodiment are denoted by the same reference numerals, description thereof is omitted, and different portions are mainly described.
  • FIG. 8A is a diagram illustrating a partial configuration of the SPFS apparatus according to the fourth embodiment.
  • the fourth embodiment it is determined whether or not there is a penetration hole in the sealing seal 11 using the imaging unit 210.
  • the photographing camera 211 is electrically connected to the control unit 160.
  • the image analysis unit 212 is provided inside or outside the photographing camera 211 and is electrically connected to the control unit 160.
  • the photographing camera 211 is not particularly limited as long as the image of the sealing seal 11 can be photographed.
  • the sealing seal 11 may be in a dark place. Therefore, the photographing camera 211 is desirably a photographing camera that can photograph even in a dark place.
  • the image analysis unit 212 is not particularly limited as long as it can analyze an image shot by the shooting camera 211.
  • the image analysis unit 212 includes a known computer or microcomputer. (Penetration hole judgment operation of SPFS device)
  • the cartridge use determination operation according to the fourth embodiment will be described focusing on the difference from the cartridge use determination operation of the SPFS device 100 according to the first embodiment.
  • FIG. 8B is a flowchart showing the contents of the cartridge use determination operation process in the fourth embodiment.
  • preparation for measurement is performed before the process shown in FIG. 8B.
  • the preparation method is the same as the method shown in step S110, but in this embodiment, not the pipette tip 170 but the imaging camera 211 is set so as to be located immediately below the cleaning liquid well 46a containing the cleaning liquid.
  • the process proceeds to the cartridge use determination operation step (step S420) in the fourth embodiment.
  • the control unit 160 activates the photographing camera 211 (step S421). Then, the control unit 160 automatically adjusts the focus or the like so that it can be determined whether or not there is a penetration hole in the sealing seal 11 on the cleaning liquid well 46a.
  • the photographing camera 211 can photograph from any position with respect to the cleaning liquid well 46a as long as it can determine whether or not there is a through hole in the sealing seal 11 on the cleaning liquid well 46a. Good.
  • a moving unit or the like for moving the photographing camera 211 may be provided in order to adjust the position of the photographing camera 211.
  • step S422 camera shooting is performed (step S422).
  • step S421 the position and focus of the photographing camera 211 are adjusted.
  • the control unit 160 photographs the sealing seal 11 on the cleaning liquid well 46a by, for example, releasing the shutter of the photographing camera 211.
  • the photographed image of the sealing seal 11 is analyzed by an image analysis unit 212 provided inside or outside the photographing camera 211, and it is automatically determined whether or not a penetration hole exists.
  • the part which plays the role which determines whether the penetration hole exists may be anywhere.
  • the image analysis unit 212 may determine, or the penetration hole determination unit 161 may determine using the image analyzed by the image analysis unit 212.
  • the use determination unit 162 determines that the inspection cartridge 10 is unused when the penetration hole determination unit 161 determines that there is no penetration hole, and the use determination unit 162 determines that the penetration hole is present when the penetration hole determination unit 161 determines that there is a penetration hole. 10 is determined to be used.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

La présente invention concerne un appareil et un procédé de détermination qui déterminent simplement et de manière fiable l'utilisation, ou non, d'une cartouche d'inspection. La présente invention concerne donc un appareil et un procédé de détermination qui déterminent l'utilisation, ou non, d'une cartouche d'inspection, l'appareil de détermination étant pourvu : d'une cartouche d'inspection comportant un puits de réactif dans lequel est contenu un réactif, et un joint d'encapsulation qui encapsule le puits de réactif ; d'une unité de détermination de trou de pénétration qui détermine si un trou de pénétration est présent dans le joint d'encapsulation ; et d'une unité de détermination d'utilisation qui, sur la base d'un résultat de détermination de l'unité de détermination de trou de pénétration, détermine que la cartouche d'inspection a été utilisée lors de la présence du trou de pénétration dans le joint d'encapsulation, et détermine que la cartouche d'inspection n'a pas été utilisée lors d'une absence du trou de pénétration dans le joint d'encapsulation.
PCT/JP2019/001483 2018-01-30 2019-01-18 Appareil et procédé de détermination Ceased WO2019150993A1 (fr)

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JP2022172555A (ja) * 2021-05-06 2022-11-17 株式会社ディスコ 加工装置
WO2023182167A1 (fr) * 2022-03-22 2023-09-28 富士フイルム株式会社 Dispositif d'inspection
KR20250007861A (ko) 2023-07-06 2025-01-14 주식회사 아이센스 분석용 카트리지 및 분석장치

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US4985631A (en) * 1988-02-16 1991-01-15 Wannlund Jon C Luminescence exposure apparatus
JPH0618531A (ja) * 1992-04-09 1994-01-25 F Hoffmann La Roche Ag 試薬キットと自動分析装置
JP2004125777A (ja) * 2002-07-31 2004-04-22 Toshiba Corp 塩基配列検出装置及び塩基配列自動解析装置
JP2009150912A (ja) * 2003-07-17 2009-07-09 Mitsubishi Kagaku Iatron Inc 自動測定用カートリッジ
JP2005300302A (ja) * 2004-04-09 2005-10-27 Tosoh Corp 照明装置および読み取り装置
WO2011161894A1 (fr) * 2010-06-22 2011-12-29 コニカミノルタホールディングス株式会社 Dispositif distributeur de liquide et puce d'essai l'utilisant
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JP2022172555A (ja) * 2021-05-06 2022-11-17 株式会社ディスコ 加工装置
JP7764140B2 (ja) 2021-05-06 2025-11-05 株式会社ディスコ 加工装置
WO2023182167A1 (fr) * 2022-03-22 2023-09-28 富士フイルム株式会社 Dispositif d'inspection
EP4481393A4 (fr) * 2022-03-22 2025-05-28 FUJIFILM Corporation Dispositif d'inspection
KR20250007861A (ko) 2023-07-06 2025-01-14 주식회사 아이센스 분석용 카트리지 및 분석장치

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